Abstract/Project Summary Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, are highly prevalent in Alzheimer's disease (AD), with increasing frequency and severity as the disease progresses. Agitation, aggression, aberrant motor behaviors (e.g., wandering, pacing), sleep disturbances and other BPSD are a significant burden for patients and their caregivers. These behavioral symptoms are linked to a faster progression of the disease, increased risk of institutionalization, and higher cost of care. The pathogenesis of BPSD is not well understood, and there are no Food and Drug Administration (FDA) approved drugs for these disabling symptoms. Antipsychotics are the most used pharmacological treatment for agitation-related symptoms in older adults with dementia, but their efficacy is low and there are serious adverse effects, including increased risk of death. Medical societies emphasize that the management of agitation-related behaviors should begin with an assessment of the underlying medical and environmental causes. In line with these clinical recommendations, the objective of this proposal is to advance knowledge on the pathogenesis of BPSD, with the long-term goal of identifying new treatments for these disabling behavioral symptoms. The primary aim of this proposal is to test the hypothesis that uric acid is associated with BPSD. The hypothesis is based on evidence that mice genetically modified to accumulate uric acid displayed more hyperactive and impulsive-like behaviors, and in humans, higher uric acid was associated with impulsivity-related traits. In clinical samples with neuropsychiatric disorders, such as bipolar disorder and the rare Lesch-Nyhan syndrome, elevated uric acid levels have been associated with behavioral symptoms akin to BPSD. Moreover, clinical trials indicate that allopurinol (a xanthine oxidase inhibitor used to reduce uric acid levels) is effective in reducing manic symptoms in bipolar patients. Support for our hypothesis that uric acid plays a role in the pathogenesis of agitation-related BPSD has translational implications. Dietary changes and medications (e.g., allopurinol) are effective in reducing levels of uric acid and could be a safer and possibly more effective treatment for BPSD than antipsychotic medications. The proposal also test the hypothesis that personality is associated with risk of BPSD, which is based on evidence that neuroticism and related traits are strong risk factors for mental health disorders. Even with the onset of dementia, individuals retain some of their personality characteristics, which are likely to shape behaviors and psychological functioning. The proposed study will advance knowledge on the role of specific personality traits related to each BPSD, and will inform interventions by fostering a person-centered approach to BPSD. The long-term goal of this research is to improve the quality of life and reduce cost of care for individuals with dementia and their caregivers.